This invention is directed at reducing cravings in mammals. More specifically the present invention is directed at reducing the cravings of a mammal to any dopamine mediated cravings including food or addictive substances.
Considerable research has been directed at obesity, nicotine addiction and substance abuse. The cost to society is very high from the health costs associated with obesity, tobacco consumption, and drug and alcohol abuse. While many individuals choose to lose weight, stop smoking and/or cease abusing drugs or alcohol, they frequently relapse into their former patterns of behavior during or shortly after they complete their treatment programs. Often this may be caused by subtle signals in the environment which initiate cravings in the individual for food or the substance which they had abused. Accordingly, it would be desirable to provide a substance which would suppress cravings for food and/or abused substances in a predisposed mammal.
The use of D.sub.1 antagonists in the treatment of drug abuse is known. U.S. Pat. Nos. 4,973,586 and 5,302,716 disclose the use of D.sub.1 antagonists in treating drug dependence. A dosage range of 0.02-10 mg/kg was suggested, with 2.0 mg/kg divided over 1-3 administrations per day being particularly preferred.
Spealman, et al., Neurochem. Int. Vol. 20 Suppl., 99147S-152S (1992) discloses that cocaine is a robust reinforcer and often is used as a standard for evaluating the reinforcing effects of other drugs. When SCH 39166 was administered to monkeys, a 3-fold or greater increase in the dose of cocaine usually was required to restore characteristic self-administration performances.
Barrett-Larimore and Spealman in Society for Neuroscience Abstracts 22(2): 92 5 (1996) reported that several compounds including the D.sub.1 antagonist SCH 39166, a D.sub.2 antagonist and a D.sub.3 /D.sub.4 antagonist all were able to attenuate the cocaine-seeking behavior in a cocaine relapse model. Clifton, 1995 and Clifton, 1991 have indicated that the D.sub.1 antagonists SCH39166 and SCH 23390 have no effect on total food intake, meal size or feeding rate up to 3 mg/kg.
Caine and Koob in The Journal of Pharmacology and Experimental Therapeutics Vol. 270, No. 1 pp. 209-218 (1994) describe tests on D.sub.1 antagonists SCH 39166 and SCH 23390 for cocaine and food self-reinforcement. D1 antagonists were found to affect cocaine self-administration.
Chausmer and Ettenberg in Pharmacology Biochemistry and Behavior Vol. 57, No. 4, pp. 681-685 (1997) conducted tests on D.sub.1 and D2 antagonists in response re-instatement properties of food reward. They found that the D.sub.2 antagonist raclopride was sufficient to block the response-reinstating effects of food reinforcement, but the D.sub.1 antagonist SCH 39166 was not.
Nathan, Breskin and Batki in CNS Drugs Jul. 10, 1998 (1) pp. 43-59 summarize results in treating cocaine addiction with various drugs.
Lancet, Volume 347 pp. 504-508 (Feb. 14, 1996) reports that haloperidol was tested for decreasing desire for an abused substance. However, this compound is reported to have had significant adverse side effects, such as dysphoria, restlessness or stiffness, which reduces the desire for individuals to take them.
It has been difficult to develop substances which inhibit craving in mammals, particularly humans, because of the lack of reliable animal models which correlate well with human behavior.
Substances which are administered to reduce craving should not produce significant physiological effects, such as stimulation of mood or elevate blood pressure or heart rate. This could result in the substitution of one abused substance for another. Compounds which dampen the desire for the abused substance also should not exacerbate the physiological symptoms of the abused substance in the event the individual relapses and takes the abused substance. Substances administered to reduce craving also should not produce significant adverse affects, such as dysphoria, restlessness or stiffness.
Accordingly, it is desirable to provide a compound and method of treatment which will be active in reducing craving for the abused substance, and which does not exacerbate the sympathetic response rate caused by the abused substance and which has favorable pharmacodynamic effects.
It also is desirable to provide a compound and method of treatment which blocks the euphoric and dysphoric effects of the abused substance.